Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: Prevention of diabetes and ectopic lipid deposition

X. Yu, S. McCorkle, May-Yun Wang, Young H Lee, J. Li, A. K. Saha, Roger H Unger, N. B. Ruderman

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

Aims/hypothesis. Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator. Methods. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat. Results. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor- deficient, diabetes-prone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle. Conclusions/interpretation. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

Original languageEnglish (US)
Pages (from-to)2012-2021
Number of pages10
JournalDiabetologia
Volume47
Issue number11
DOIs
StatePublished - Nov 2004

Keywords

  • AICAR
  • AMP-activated protein kinase
  • Acetyl CoA carboxylase
  • Leptin
  • Malonyl CoA
  • Triglycerides

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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